Modulation with cytokines of radiation injury: suggested mechanisms of action.
Cytokines, hormonelike proteins, produced by stimulated cells and tissues, were found to protect mice against lethal hematopoietic failure caused by ionizing radiation. Radioprotection was achieved by pretreatment with interleukin-1 (IL-1), tumor necrosis factor (TNF), IL-12, or stem cell factor (SCF) at 18 to 24 hr before irradiation. Pretreatment with antibodies to these cytokines rendered the mice more susceptible to radiation lethality, indicating that these cytokines play a role in innate resistance to radiation. In contrast, treatment with tumor growth factor beta (TGF-beta), a cytokine that inhibits cycling of primitive hematopoietic progenitors, sensitized mice to radiation lethality. The schedule of IL-1 administration was critical to its radioprotective effect. Evidence was obtained that this may be based on the induction of additional cytokines by IL-1. The radioprotective effects of cytokines can be based on induction of cycling of primitive progenitor cells (IL-1, SCF), prevention of apoptosis (SCF), and induction of scavenging proteins and enzymes (IL-1, TNF) that reduce oxidative damage. In contrast, radiosensitizing effects may be due to inhibition of progenitor cycling (TGF-beta) or enhanced progenitor cell apoptosis (TGF-beta). Thus, the insights gained from such studies at the whole-animal level promise a better understanding of the membrane and intracellular events associated with radiation damage and repair of such damage.
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Office of International Health Programs, U.S. Department of Energy, Germantown, MD 20874, USA. ruth.neta@eh.doe.gov
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D016207:Cytokines / Q000502:physiology / Q000627:therapeutic use*; D004064:Digestive System / Q000187:drug effects / Q000528:radiation effects; D007378:Interleukins / Q000627:therapeutic use; D051379:Mice; D011833:Radiation Injuries, Experimental / Q000503:physiopathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D019089:Stem Cell Factor / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use
D016207:Cytokines; D007378:Interleukins; D011837:Radiation-Protective Agents; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha